Dr. Anthony Gerber is a pulmonary and critical care physician with a well-defined interest in developmental biology that was fostered as a member of the medical scientist training program at the University of Washington. His overall career objective is to combine his clinical and basic science interests through studying the relationship between developmental pathways and lung disease in an academic medical center. This proposal is constructed to provide the framework to achieve that goal. Through a series of specific aims, Dr. Gerber will test several hypotheses regarding the role of the hedgehog (Hh) pathway, a critical developmental control network, in the lung. Specifically, he will explore the effects of transgenic misexpression of the Hh regulated transcription factor, Gli1, in the lung epithelium and mesenchyme. This will test the hyopthesis that Gli1 regulates patterning, proliferation, and differentiation in the developing lung. The hypothesis that the effects of Hh signaling in the lung vary depending on timing will be tested using temporal regulation of Gli1 mis-expression. Microarrays will also be used to identify targets of Hh signaling in the lung to test the hyopthesis that distinct subsets of genes respond to the Hh signal at different times;ultimately the effects of Gli1 on gene activation and lung injury will be assessed using mouse and cell culture models. The relevance of the proposed work to lung disease is based on the general notion that developmental pathways are activated in disease, coupled with specific recent observations that the Hh pathway is activated in response to lung injury and is expressed in lung cancer and pulmonary fibrosis. Additionally, this proposal is designed to complement Dr. Gerber's prior laboratory experience and provide him with the requisite technical and intellectual background in lung development to function as an independent investigator. A committee of physicians and scientists will oversee Dr. Gerber's progression towards independence;his scientific development will also be enriched through attendance at several seminar series at UCSF, departmental retreats, and national meetings. UCSF is committed to the development of careers in academic medicine, and at the end of the grant period, Dr. Gerber will be prepared to embark on a career as an independent physician scientist investigating developmental pathways that are active in lung disease.